Recent clinical and preclinical, and human genetic studies suggest that selective positive allosteric modulators (PAMs) of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor have exciting potential as a novel approach for treatment of schizophrenia. We found that highly selective mGlu1 PAMs exert their antipsychotic-like effects in animal models by selectively inhibiting dopamine (DA) release in the striatum but not in extrastriatal regions, where inhibition of DA signaling could contribute to adverse effects of existing antipsychotic agents. Furthermore, we present exciting new data showing that mGlu1 PAMs have specific actions within the prefrontal cortex (PFC) that can reverse pathophysiological changes in specific cortical circuits that are disrupted in schizophrenia patients, and can reverse specific cognitive and social deficits in rodent models. Thus, mGlu1 PAMs could provide robust antipsychotic efficacy through actions of DA signaling, and may also improve some negative symptoms and cognitive deficits in schizophrenia patients by reducing pathophysiological changes in specific cortical circuits. It will now be important to optimize highly selective mGlu1 PAMs that are suitable for advancing to clinical development to allow clinical studies to directly assess the utility of these compounds as a novel strategy for treatment of schizophrenia. We recently made a major breakthrough in discovery and optimization of multiple highly selective mGlu1 PAMs that have excellent drug- like properties. These compounds provide exciting new drug leads that can provide the basis of a focused effort to optimize novel mGlu1 PAMs that are suitable for advancing to preclinical and clinical development. We have been highly successful in optimizing multiple selective ligands for other mGlu receptors and other GPCR subtypes as drug candidates that are now advancing in preclinical and clinical development. This places us in an excellent position to optimize selective mGlu1 PAMs as drug candidates for treatment of positive symptoms associated with schizophrenia and to further assess the potential utility of these compounds in reversing specific negative symptoms and cognitive deficits. We now propose a series of studies in which we will optimize highly selective mGlu1 PAMs suitable for preclinical proof of concept studies and that have the properties required so that they can subsequently be advanced IND-enabling studies and clinical development.